Abstract Stroke is the fourth leading cause of death in the United States and the number one cause of serious, long term disability. Of the nearly 800,000 annual strokes, approximately 25% will be recurrent events. Unfortunately, recurrent strokes are more deadly and most likely to cause disability when compared to a first stroke. Genetic studies focusing on recurrent stroke have been extremely limited. We have identified two novel gene regions associated with recurrent stroke and aim to use next generation DNA sequencing (NGS) to fine-map these regions to hone in on the likely causal variants. For 182 recurrent stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, we will utilize NGS platforms to identify all genetic variants across 1.5 Mb spanning the two novel gene regions associated with recurrent stroke. High priority variants will be genotyped in all 2,100 VISP participants and analyzed for association with recurrent stroke. NGS is a cutting edge technology that provides a powerful approach to identify novel and important genetic contributors to recurrent stroke, a phenotype that has been poorly studied. This approach may allow improved personalization of risk assessment and targeted prevention. Moreover, VISP participants include both African Americans (AA) and European Americans, therefore this proposal may identify genetic risk variants specific to populations of African descent that might not otherwise be identified in other studies focused primarily on populations of European ancestry. These variants may help address why African Americans have nearly 2x greater risk of suffering a stroke, and are more likely to die following a stroke, as compared to European Americans. Furthermore, these findings may have broader implications by providing insight on other issues influencing recurrent stroke such as the ability to control manageable risk factors (e.g. hypertension and atrial fibrillation) and likewise one?s response to treatment for anticoagulation, antiplatelet, and antihypertensive medications. Moreover, these finding may reflect post stroke treatment response to tissue plasminogen activator (tPA), the only FDA approved treatment for ischemic stroke. Aligned with the goals of the NIH Academic Research Enhancement Award (AREA) Program (R15), we aim to explore a significant research question while exposing students to research, in particular learning cutting edge skills in Genomics, Population Genetics, Biotechnology techniques involving NGS library preparations, and Bioinformatics skills focused on analyzing NGS data and performing statistical analyses for genetic studies.